In recent years, much research has been done in developing systems using polymeric compositions for the programmed release of active agents, especially drugs, over periods of time. The purpose of these systems is to dispense the agent at a controlled, and if desired, constant rate in order, as in the case of pharmeutical agents or drugs, to improve therapy by presenting the drug in the most beneficial and reliable manner, with a minimum possibility of complications from the drug or from failure to comply with the therapeutic regimen. For example, see Folkman, et al, in Journal of Surgical Research, Vol. 4, pages 139 to 142, 1964; U.S. Pat. No. 3,832,252 issued to Higuchi, et al; and U.S. Pat. No. 3,854,480 issued to Zaffaroni. Both of these patents are assigned to the Alza Corporation of Palo Alto, Calif.
While the above systems represent an extraordinary advancement in the art, and while they possess ideal kinetics for effectively delivering low molecular weight agents, a limiting feature associated with these systems is they are not designed to deliver agents which possess macromolecular structures. This is so since such systems operate, in the case where the polymer matrix is not absorbable in the environment, by diffusion which fundamentally depends on the agent permeating at a controlled rate through the polymer. Inasmuch as macromolecular agents do not diffuse through polymeric materials at rates which are high enough to be used to advantage, these prior art systems cannot be used satisfactorily for delivering macromolecular agents. It is also disclosed in U.S. Pat. Nos. 3,896,819 and 3,948,254, issued to Zaffaroni and assigned to the Alza Corporation, that certain large molecules can be released by the delivery devices as defined therein; however, the devices of these patents are structurally distinct, operate differently, and accordingly they do not provide the beneficial release kinetics as obtained with the system of this invention.
It is apparent from the foregoing presentation that a critical need exists for systems that can successfully deliver macromolecular agents. The prior art has made systems that seemingly attempted to satisfy this need, but the results obtained have not led to acceptable application of the systems. For example, Davis in the "Control of Diabetes with Polyacrylamide Implants Containing Insulin", Experientia, Vol. 28, page 348, 1972 and in "Diffusion in Polymer Gel Implants", Proc. Nat. Acad. Sci., USA, Vol. 71, pages 3120 to 3123, 1974 disclosed gels formed of crosslinked, hydrophilic polyacrylamide and polyvinylpyrrolidone polymers containing protein solutes used as implants that release the solutes by simple diffusion over a limited period of time. However, these single phase gel compositions did not lead to systems having accaptable release properties because the duration of release depends on the density of the gel which property is difficult to control with standard manufacturing techniques, and also because the rate of solute release follows an exponential time course until depletion of the solute is virtually complete. Similar attempts to release macromolecules were disclosed by Gimbrone, et al in "Tumor Growth and Neovascularization: An Experimental Model Using the Rabbit Cornea", in J. Nat. Can. Inst., Vol. 52, pages 413 to 427, 1974, with the use of polyacrylamide gels for delivering tumor angiogenesis factor, and by Gould et al, in U.S. Pat. No. 3,576,760. In the patent, Gould et al disclosed the entrapment of enzymes in water soluble acrylic polymers which compositions release the enzyme upon contact with water by virtue of dissolution of the water soluble polymer. None of the prior art references has lead to an acceptable system for releasing macromolecular structures, particularly biologically active molecules of increased size and weight at controlled rates over prolonged periods of time.
Folkman et al, U.S. Pat. No. 4,164,560, hereby incorporated by reference, describes a method of making such a body by forming a liquid mixture containing the polymer, the active substance, and an organic solvent capable of dissolving the polymer, and solidifying the liquid mixture to form the polymeric body. Folkman et al have shown that controlled release systems for macromolecules can be formulated by dissolution of ethylene-vinyl acetate copolymer in an organic solvent (dichloromethane), adding powdered macromolecule, casting the mixture in a mold at low temperature, and vacuum drying. However, the addition of solvent during the casting procedure may cause denaturation of certain macromolecules. In addition, the removal of the casting solvent in the drying step is time consuming and leads to shrinkage and possibly shape distortion of the matrix. Therefore, it would be highly desirable to provide a process for making these release systems without the need for a solvent.